Intermediate AAT deficiency as found in MZ phenotypes have an unknown predisposition to COPD. Studies of a population of 601 subjects during the last 2 years of our grant have confirmed our original hypothesis that MZ cigarette smokers have an accelerated decrease in pulmonary function compared to MM smokers, particularly over age 40. We now want to extend these prevalence studies to include the 600 subjects now being identified by the MRFIT project at our research institute. In addition, we propose to do 5 year incidence studies on this population as well as on some of the 124 MZ, 11 ZZ, 4 SS, 5 SZ, and on over 100 MS phenotypes already identified during the past 3 years. Cigarette smokers, ages 35 to 55, will be particularly chosen for serial studies as they are most likely to develop COPD and therefore will define the early and perhaps accelerated pathophysiologic phases of COPD. Other etiologic mechanisms to be investigated are the transport of AAT in the lung and the level of proteases in alveolar macrophages obtained by bronchial lavage in selected paradoxical groups: a) Smokers without disease, and b) Non-smokers with disease. The biochemical basis of AAT deficiency remains undefined. We have isolated the M-protein, and preliminary work is encouraging for the separation of the Z-protein as well. The purified proteins and carbohydrate modified derivatives will be characterized chemically and immunologically and their catabolism in MM and ZZ phenotypes will be investigated in order to determine: 1) Is the sialic acid content the principal difference between M and Z proteins and is this residue more important in controlling the release or the catabolism of AAT?; 2) Can the catabolism of M protein be a) increased by removing sialic residues, or b) decreased by blocking galactosyl residues, thus prolonging plasma half-life and increasing the feasibility of replacement therapy?; 3) Do the M and Z protein have common immunological properties and does alteration in carbohydrate residues alter antigenicity? These biochemical studies on AAT should have general application to other glycoproteins as well.